Basic ethers of 4-hydroxy-benzophenones acting as beta-blocking agents

ABSTRACT

Basic ethers of 4-hydroxy-benzophenones acting as beta-blocking agents,  sting from 4-hydroxy-benzophenones and, by reacting them with epichlorohydrin, transforming them into the corresponding 4-O(2&#39;, 3&#39;-epoxy-propoxy) derivatives, then reacting with isopropylamine, obtaining the substances according to the invention which can be defined as 4 (gammaisopropylamino-betahydroxypropoxy) benzophenones, wherein the 3 and 4&#39; positions can be represented by: H, Cl and acetyl.

The present invention relates to new substances having beta-blocking activity, and particularly basic ethers of 4-hydroxy-benzophenones. There are known from quite a time beta-blocking agents having as general formula: ##STR1## wherein aryl is almost always phenyl, sometimes naphthyl and recently heterocyclic residues.

Alkyl is C1-C4, particularly isopropyl.

The present invention surprisingly proved that, if aryl was equal to benzophenone, and in particular benzophenone 4'-halogen substituted and/or 2-acetyl substituted, some characteristics of the substances were improved with respect to what already known, especially as to the sorption, distribution and elimination rhythms, with the considerable advantages deriving thereof.

Even the salts of the resulting substances obviously fall within the ambit of the present invention, and particularly hydrochlorides, bromhydrates, sulfates, tartrates, lactates and benzoates.

It is an integral part of the present invention a process starting from 4-hydroxy-benzophenones (I) which, through a reaction with epichlorohydrin, are transformed into the corresponding 4-O(2', 3' epoxy-propoxy) derivatives (II), and then are reacted with isopropylamine to obtain the substances according to the invention which are 4-(gamma-isopropylamino-betahydroxypropoxy) benzophenones (III).

In these molecules the 3-position (ortho with respect to the basic alkyl chain) and the 4' position can be represented by H, Cl and acetyl.

The process according to the invention can be represented by the following synthesis: ##STR2##

It is to be noted that when passing from II to III it is possible to alternatively sever the bond of the epoxidic function and use the halogen gamma betahydroxy-propoxy derivative to obtain, always through a reaction with isopropylamine, the product III.

The present invention could be better understood through the following examples, showing the carrying-out of the process according to the invention.

The pharmacological and clinical effects of known Beta-blocking agents are thoroughly illustrated in these texts:

(1) Clinical pharmacology basic principles in therapeutics, 11 ed. by Kenneth L. Melmon, Havard, F. Morrelli-Publishing Co. Inc.--edited MacMillan, New York 1978, Pagg. 193-196.

(2) The Pharmacological Basis of Therapeutics, 5th ed. edited by Louis S. Goodman and Alfred Gilman, 1975, pagg. 546-552, Publishing Co. Inc.--edited MacMillan.

The products according to invention have been experimented by test called "Blood Pressure and Cardiac Rate Recording in Rabbit After Isoproterenol Injection Intravenous".

By this test the products according to the invention, were found to have same activity as known beta-blocking agents with lower average dosages of 10-20%.

EXAMPLE 1 Preparation of 4-(2',3'-epoxy-propoxy) benzophenones

1 mole of a suitable 4-hydroxybenzophenone is diluted by heating in anhydrous ethanol: while keeping under stirring, a mole of methoxide Na is added. After stirring for 20', the solution is dry concentrated under vacuum. The residue is mixed with 2.5 l of dimethylformamide and 1.5 mole of epichlorohydrin is added thereto; the whole is kept under stirring and heated for 4 hours at 100° C.

Decolorizing carbon is added and, after filtration, the whole is dry concentrated in vacuum. The resulting residue is recrystallized from hexane or aqueous ethanol. The yields range from 75 to 80% of the expected yield.

Starting, e.g., from 4-p.-chlorobenzoyl-phenol and acting as described above, there is obtained 4-chloro-4'-(2,3-epoxy-propoxy)-benzophenone in the form of white crystalline powder (M.P. 110°-12°), soluble in ethanol, acetone and dioxane, insoluble in water, hexane and petroleum ether.

EXAMPLE 2 Preparation of 4-(2'-oxy-3'-isopropylamino-propoxy) benzophenones

1 mole of a suitable 4-(2,3-epoxy-propoxy) benzophenone (II) is diluted in the minimum alcohol volume, and 3 moles of monoisopropylamine are added. The solution is heated for 8 hours at 35°-40° C., then is left alone overnight at ambient temperature.

After treatment with decolorizing carbon, the bulk mass is dry concentrated in a rotating vacuum evaporator.

The residue is diluted in 10% hydrochloric acid; while keeping at 5°-10° C. and stirring, the solution is alkalized by slowly adding thereto a 20% solution of Na hydrate. After some hours, the precipitate is filtered and washed with water. After drying, the product is recrystallized from ethyl-hexane acetate.

The yields of the purified product are 70-75% of the expected yield.

For instance, reacting 4-chloro-4'-(2,3-epoxy-propoxy)-benzophenone with isopropylamine, is obtained 4-chloro-4'-(2-oxy-3-isopropylamino-propoxy) benzophenone, in the form of a white crystalline powder (M.P. 94°-95°), soluble in ethyl acetate ethanol and diethyl ether, insoluble in H₂ O, hexane and petroleum ether.

EXAMPLE 3 Preparation of 4-(2'-oxy-3'-isopropylamino-propoxy)-benzophenones benzoate

1 mole of 4-(2'-oxy-3'-isopropylamino-propoxy)-benzophenone is diluted in the minimum absolute alcohol volume, under stirring and heating at 50° C. To the resulting solution there is added, in small doses, one mole of benzoic acid.

After stirring at 50° C. for half an hour, the solution is concentrated to dryness under vacuum. The resulting residue is purified through crystallization from ethyl acetate.

The yields are 85-90% of the expected yields.

EXAMPLE 4 Preparation of 4-(2'-oxy-3'-isopropylamino-Propoxy)-Benzophenones Hydrochloride

1 mole of 4-(2'-oxy-3'-isopropylamino-propoxy)-benzophenone is diluted in the minimum absolute ethanol volume. By externally cooling, the solution is saturated with dry gaseous HCL.

Always cooling, 3 volumes of diethyl ether are added. The resulting precipitate is filtered and washed with diethyl ether. By treating, e.g., 4-chloro-4'-(2-oxy-3-isopropylamino-propoxy)-benzophenone with HCL, there is obtained the corresponding hydrochloride, in the form of white crystals with M.P. 162°-164°, soluble in H₂ O and ethanol, insoluble in diethyl ether and chloroform.

Although only some application of the invention have been described, one skilled in the art could easily envisage several changes and variations, which however, must all fall within the ambit of the present invention.

For instance, by treating 4-(2'-oxy-3'-isopropylamino-propoxy)-benzophenone (white crystals with melting point 103°-104°), with equimolecular quantity of benzoic acid, there is obtained the corresponding salt in the form of white powder (M.P. 139°-140°), soluble in H₂ O and acetone, insoluble in benzol, diethyl ether and chloroform. 

What we claim is:
 1. A compound of the formula: ##STR3## wherein R is hydrogen or chlorine and R¹ is hydrogen or acetyl, and pharmaceutically acceptable salts thereof.
 2. A pharmaceutical beta-blocking composition containing, as an active ingredient thereof, a compound of the formula: ##STR4## wherein R is hydrogen or chlorine and R¹ is hydrogen or acetyl, or its pharmaceutically acceptable salts. 